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Flow-sorting and Exome Sequencing of the Reed-Sternberg Cells of Classical Hodgkin Lymphoma
Published on: June 10, 2017
Cancer Immunotherapy and the Immune Response in Hodgkin Lymphoma
Christoph Renner1, Frank Stenner2
1Department of Biomedicine, University Basel, Basel, Switzerland.
Insights
Classical Hodgkin lymphoma (cHL) involves immune suppression via PD-L1/PD-L2 on tumor cells, hindering T-cell activity. Targeting these pathways and CD30 offers promising immunotherapeutic strategies for cHL patients.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Classical Hodgkin lymphoma (cHL) is characterized by sparse Hodgkin-Reed-Sternberg (HRS) cells within an inflammatory microenvironment.
- Despite the inflammatory infiltrate, cHL exhibits impaired cellular immunity and a poor anti-tumor response.
- This immune evasion is primarily driven by high PD-L1 and PD-L2 expression on HRS cells, which inhibits T-cell function.
Purpose of the Study:
- To elucidate the mechanisms of immune suppression in cHL.
- To identify key molecular targets for novel immunotherapeutic strategies in cHL.
- To evaluate the potential of targeting the PD-1/PD-L1 pathway and CD30 antigen for cHL treatment.
Main Methods:
- Analysis of immune cell responses and tumor microenvironment in cHL patients.
- Investigation of PD-L1/PD-L2 overexpression mechanisms, including 9p24.1 gene amplification and Epstein-Barr virus association.
- Development and assessment of therapeutic strategies targeting the PD-1/PD-L1 axis and CD30.
Main Results:
- High expression of PD-L1 and PD-L2 on HRS cells was identified as a key mechanism of immune suppression in cHL.
- PD-L1/L2 overexpression is linked to 9p24.1 locus amplification and/or Epstein-Barr virus infection in approximately 40% of cHL cases.
- Monoclonal antibody blockade of the PD-L1/L2-PD-1 pathway demonstrated significant and durable tumor responses in cHL patients.
- CD30-targeted therapies, including immunotoxins and bispecific antibodies, have shown efficacy, with one approved for high-risk or relapsed cHL.
Conclusions:
- Understanding the immune suppressive pathways in cHL, particularly PD-L1/L2-mediated T-cell inhibition, is crucial for therapeutic development.
- Targeting the PD-1/PD-L1 pathway represents a highly effective immunotherapeutic strategy for cHL, leading to long-lasting responses.
- CD30-directed therapies offer additional effective treatment options for cHL, especially in relapsed or refractory settings.
- cHL serves as a model for successful immunotherapeutic development due to identified pathomechanisms and target antigens.
Abstract:
Patients with classical Hodgkin lymphoma (cHL) have an impaired cellular immune response as indicated by an anergic reaction against standard recall antigens and a diminished rejection reaction of allogeneic skin transplant. This clinical observation can be linked to the histopathological feature of cHL since the typical pattern of a cHL manifestation is characterized by sparse large CD30+ tumor-infiltrating Hodgkin-Reed-Sternberg (HRS) cells that are surrounded by a dense inflammatory immune microenvironment with mixed cellularity. Despite this extensive polymorphous inflammatory infiltrate, there is only a poor antitumor immune response seen to the neoplastic HRS cells. This is primarily mediated by a high expression of PD-L1 and PD-L2 ligands on the HRS cell surface which in turn antagonizes the activity of programmed death-1 (PD-1) antigen-positive T cells. PD-L1/L2 overexpression is caused by gene amplification at the 9p24.1 locus and/or latent Epstein-Barr virus infection present in around 40% of cHL cases. The blockade of the PD-L1/L2-PD-1 pathway by monoclonal antibodies can restore local T cell activity and leads to impressive tumor responses, some of which are long lasting and eventually curative. Another feature of HRS cells is the high CD30 antigen expression. Monoclonal antibody technology allowed for the successful development of CD30-specific immunotoxins, bispecific antibodies, and reprogrammed autologous T cells with the first one already approved for the treatment of high risk or relapsed cHL. Altogether, the discovery of the described pathomechanism of immune suppression and the identification of preferential target antigens has rendered cHL to be a prime subject for the successful development of new immunotherapeutic approaches.
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